Chapter 7

Management of Bleeding
Complications
Marcel Levi

Introduction
Anticoagulant agents are often used for prevention and
treatment of a wide range of cardiovascular diseases, includ-
ing acute coronary syndromes. The most frequently used
anticoagulants are heparin or its derivatives, vitamin K
antagonists (such as warfarin or coumadin) and antiplatelet
agents, including aspirin and thienopyridine derivatives,
such as clopidogrel or prasugrel. A myriad of clinical studies
have demonstrated that these agents (alone or in combina-
tion) can prevent or treat acute or chronic thrombo-embolic
complications, such as in patients with atrial fibrillation or
prosthetic heart valves, after myocardial infarction, percuta-
neous coronary interventions, or ischemic stroke, and in
patients with venous thrombosis or pulmonary embolism [1].
The most important complication of treatment with antico-
agulants is hemorrhage, which may be serious, may cause

M. Levi, MD, PhD ()

Department of Medicine,
Academic Medical Center,
University of Amsterdam,
Meibergdreef 9, Amsterdam, 1105 AZ,
The Netherlands
e-mail: m.m.levi@amc.uva.nl

P. Avanzas, P. Clemmensen (eds.), Pharmacological Treatment 213

of Acute Coronary Syndromes, Current Cardiovascular Therapy,
DOI 10.1007/978-1-4471-5424-2_7,
© Springer-Verlag London 2014
214 M. Levi

long-term debilitating disease, or may even be life-threaten-

ing [2, 3]. In a very large series of 34,146 patients with acute
ischemic coronary syndromes, anticoagulant-associated
bleeding was associated with a 5-fold increased risk of death
during the first 30 days and a 1.5-fold higher mortality
between 30 days and 6 months [4]. Major bleeding was an
independent predictor of mortality across all subgroups that
were analyzed. In some clinical situations the incidence of
serious bleeding complications may annihilate or even over-
whelm the efficacy of antithrombotic agents, as has been
shown in the secondary prevention of patients with ischemic
stroke by vitamin K antagonists [5]. Nevertheless, in many
situations clinical studies show a favorable balance between
efficacy and safety in favor of anticoagulant treatment.
However, if severe bleeding occurs or if a patient needs to
undergo an urgent invasive procedure, such as emergency
surgery, it may be necessary to reverse the anticoagulant
effect of the various agents [6]. Depending on the clinical
situation, i.e. the severity of the bleeding or the urgency and
estimated risk of the invasive procedure, this reversal may
take place in a few hours, but in some cases immediate
reversal is necessary (Table 7.1) [7, 8]. Generally, each
(immediate) reversal of anticoagulant treatment needs also
to take into consideration the indication for the antithrom-
botic agents. For example, the interruption of combined
aspirin and clopidogrel treatment in a patient in whom
recently an intracoronary stent has been inserted will mark-
edly increase the risk of acute stent thrombosis with conse-
quent downstream cardiac ischemia or infarction. Likewise,
in a patient with a prosthetic mitral valve and atrial fibrilla-
tion, interruption of vitamin K antagonists may increase the
risk of valve thrombosis and cerebral or systemic embolism.
Each of these specific clinical situations requires a careful
and balanced assessment of the benefits and risks of revers-
ing anticoagulants (and potential strategies to keep the
period of reversal as short as possible). In this chapter, we
will describe the various strategies to reverse the anticoagu-
lant effect of currently most widely used antithrombotic
agents and the new generation of anticoagulants.
Table 7.1 Reversal of anticoagulant effect of different agents
Time until restoration of
hemostasis after cessation
of therapeutic dose Antidote Remark
Chapter 7.

Heparin 3–4 h Protamine sulphate 25–30 mg; 1 mg of protamin per 100 anti-Xa
immediate reversal units given in the last 2–3 h
LMW heparin 12–24 h (Partially) protamine sulphate 1 mg of protamine per 100
25–50 mg; immediate reversal anti-Xa units given in the last 8 h
Pentasaccharides Fondaparinux: 24–30 h Recombinant factor VIIa 90 ug/kg; Based on laboratory end-points,
immediate thrombin generation no systematic experience in
Idraparinux: 5–15 days bleeding patients
Vitamin K Acenocoumarol: 18–24 h Vitamin K i.v: reversal in 12–16 h Dose of vitamin K or PCC’s
antagonists depend of INR and bodyweight
Warfarin: 60–80 h Vitamin K orally: reversal in 24 h
Phenprocoumon: 8–10 days PCC’s: immediate reversal
Oral thrombin Dependent of compound, Prothrombin complex concentrates Based on laboratory end-points,
and factor Xa usually within 12 h or recombinant factor Xa for Xa no systematic experience in
inhibitors inhibitors, unsure for IIa inhibitors bleeding patients
Management of Bleeding Complications

(continued)
215
Table 7.1 (continued)
216

Time until restoration of

hemostasis after cessation
of therapeutic dose Antidote Remark
Aspirin 5–10 days (time to produce DDAVP (0.3–0.4 ug/kg) and/or Cessation not always required,
M. Levi

unaffected platelets) platelet concentrate; reversal in also dependent on clinical

15–30 min situation and indication
Clopidogrel 1–2 days Platelet concentrate, possibly in Cessation not always desirable,
combination with DDAVP (0.3–0.4 also dependent on clinical
Prasugrel situation and indication
ug/kg); reversal in 15–30 min
LMW heparin low molecular weight heparin, PCC prothrombin complex concentrate, DDAVP de-amino d-arginin vasopres-
sin or desmo pressin
 Chapter 7. Management of Bleeding Complications 217

Incidence and Risk Factors for Bleeding

in Patients on Anticoagulants
In well-controlled patients in clinical trials treatment with
heparin or vitamin K antagonists (VKA’s) increase the risk of
major bleeding by 0.5 %/year and the risk of intracranial hem-
orrhage by about 0.2 %/year [9]. The most important risk fac-
tor for hemorrhage in users of anticoagulants is the intensity
of the anticoagulant effect [9]. Studies indicate that with a
target INR of >3.0 the incidence of major bleeding is twice as
large as in studies with a target INR of 2.0–3.0 [10]. In a meta-
analysis of studies in patients with prosthetic heart valves, a
lower INR target range resulted in a lower frequency of major
bleeding and intracranial hemorrhage with a similar anti-
thrombotic efficacy [11]. A retrospective analysis of outpa-
tients using warfarin who presented with intracranial
hemorrhage demonstrated that the risk of this complication
doubled for each 1 unit increment of the INR [12]. Patient
characteristics constitute another important determinant of
the bleeding risk bleeding. Elderly patients have a 2-fold
increased risk of bleeding [13] and the relative risk of intracra-
nial hemorage (in particular at higher intensities of anticoagu-
lation) was 2.5 (95 % CI 2.3–9.4) in patients >85 years
compared to patients 70–74 year old [14]. Recently, genetic
factors have been identified that may affect the risk of bleed-
ing. Common polymorphisms in the P450 CYP2C9 enzyme
were found to be associated with slow metabolism of VKA’s
and (possibly) a higher risk of bleeding [9, 15]. Other genetic
factors that may influence the requirement of VKA’s are vari-
ants in the vitamin K epoxide reductase complex subunit 1
gene (VKORC1) [16]. Co-morbidity, such as renal or hepatic
insufficiency, may also significantly increase the risk of bleed-
ing. A case-control study in 1,986 patients on VKA’s showed
that this comorbidity increased the risk of bleeding by about
2.5 [17]. Another very important determinant of the risk of
bleeding is the use of other medication, in particular agents
affecting platelet function. Two meta-analyses, comprising 6
trials with a total of 3,874 patients and 10 trials with a total of
218 M. Levi

5,938 patients, found a relative risk of major bleeding when

VKA’s or heparin were combined with aspirin of 2.4 (95 % CI
1.2–4.8) and 2.5 (95 % CI 1.7–3.7), respectively [18, 19]. A
population-based case-control study confirmed the high risk
of upper gastro-intestinal bleeding in patients using VKA’s in
combination with aspirin and/or clopidogrel [20]. Non-
steroidal anti-inflammatory agents (NSAIDs) are also associ-
ated with an enhanced risk of gastro-intestinal bleeding. The
combined use of VKA’s and NSAIDs may result in an 11-fold
higher risk of hospitalization for gastro-intestinal bleeding as
compared to the general population [21]. This risk is not sig-
nificantly lower when using selective inhibitors of COX-2 [22].

Heparin and Low Molecular Weight

(LMW) Heparin
Heparin and heparin derivatives act by binding to antithrom-
bin and thereby about 1,000-fold potentiating the anticoagu-
lant effect of this endogenous inhibitor towards thrombin
and factor Xa (and some other coagulation factors). Heparin
has a relatively short half life of about 60–90 min and there-
fore the anticoagulant effect of therapeutic doses of heparin
will be mostly eliminated at 3–4 h after termination of con-
tinuous intravenous administration [23]. The anticoagulant
effect of high dose subcutaneous heparin, however, will take
a longer time to abolish. If a more immediate neutralization
of heparin is required, intravenous protamine sulphate is the
antidote of choice. Protamine, derived from fish sperm, binds
to heparin to from a stable biologically inactive complex.
Each mg of protamine will neutralize approximately 100
units of heparin. Hence, the protamine dose in a patient on a
stable therapeutic heparin dose of 1,000–1,250 U/h should be
about 25–30 mg (sufficient to block the amount of heparin
given in the last 2–3 h). The maximum dose of protamine is
50 mg. Since the half-life of protamine is only about 10 min,
the reversal of therapeutic dose subcutaneous heparin
requires a repeated infusion of protamine sulphate
 Chapter 7. Management of Bleeding Complications 219

(e.g. repeated after 1 h). The effect of protamine can be moni-

tored by measuring the activated partial thromboplastin time
(aPTT), which should normalize after its administration.
The reversal of LMW heparin is more complex, as prot-
amine sulphate will only neutralize the anti-factor IIa activity
and has no or only partial effect on the smaller heparin frag-
ments causing the anti-factor Xa activity of the compound
[24, 25]. The net effect of protamine reversal of LMW heparin
is not completely clear. There are no clinical studies that have
systematically studied this and small case series and experi-
mental animal studies show contradictory results [25–27]. As
the aPTT is not useful as a monitoring assay when using
LMW heparin, it can also not be used for the monitoring of
the neutralizing effect of protamine. Given the relatively long
half-life of LMW heparin, the lack of an adequate strategy to
reverse its anticoagulant action may sometimes cause a prob-
lem in clinical situations. A practical approach is to give 1 mg
of protamine per 100 anti-factor Xa units of LMW heparin
given in the last 8 h (whereas 1 mg of enoxaparin equals 100
anti-factor Xa units). If bleeding continues, a second dose of
0.5 mg per 100 anti-factor Xa units can be given.
The most important adverse effect of protamine is an
allergic response, including hemodynamic and respiratory
problems [28]. Most adverse reactions can be prevented or
minimized by slowing the rate of administration of the drug
or by pretreatment with steroids and antihistamines. Risk fac-
tors for an adverse reaction are sensitivity to fish (as may
occur in traditional fishermen that are often exposed to fish
proteins when cutting themselves), a history of vasectomy
(which may demolish the blood-testis barrier with conse-
quent formation of anti-semen antibodies) and a history of
receiving protamine sulphate containing insulin. Initial
reports that the use of protamine sulphate could lead to an
increased risk of rebound thrombosis, in particular ischemic
stroke [29, 30], were not confirmed in a recent randomized
controlled study [31].
There are some other strategies to reverse (mostly unfrac-
tionated) heparin, such as platelet factor-4, heparanase, or
220 M. Levi

extracorporeal heparin-removal devices, but none of these

approaches have been properly evaluated and they are not
currently approved for clinical use [32–34].

Pentasaccharides
Pentasaccharides are recently developed synthetic com-
pounds that effectively bind and potentiate antithrombin to
block factor Xa. Since they lack the additional glycosamino-
glycan saccharide residues to bind to thrombin, it has an
effect on factor Xa exclusively. The prototype pentasaccha-
ride (and the only one approved for clinical use so far) is
fondaparinux. Another pentasaccharide that is currently
under study is idraparinux. The main difference between
these two agents is the elimination half-life, which is 15–20 h
for fondaparinux and 5½ days for idraparinux. This means
that idraparinux can be administered once weekly, which
renders the subcutaneous route of administration less cum-
bersome. Pentasaccharides were shown to be effective in the
prophylaxis and treatment of venous thromboembolism and
are currently evaluated in other types of thrombosis [35]. The
(very) long half-life of pentasaccharides necessitates the
availability of a suitable antidote if major bleeding compli-
cates the treatment, which may especially occur in patients
that are treated with therapeutic doses of this type of antico-
agulation. So far, there is no antidote for pentasaccharides
that has been studied in controlled clinical studies [36]. The
only agent that has been systematically evaluated to reverse
the anticoagulant effect of pentasaccharides is recombinant
factor VIIa (rVIIa). Two randomized placebo-controlled
studies in healthy volunteers have tested the hypothesis that
rVIIa may be useful as a suitable antidote for pentasaccha-
ride anticoagulation [37, 38]. In the first study 16 subjects
were treated with therapeutic doses of the pentasaccharide
fondaparinux and after 2 h (at the time of maximal antico-
agulation) challenged with rVIIa or placebo. Injection
of rVIIa (90 μg/kg) after fondaparinux normalized the
 Chapter 7. Management of Bleeding Complications 221

prolonged aPTT and prothrombin time (PT) and reversed

the decrease in prothrombin activation fragments 1 + 2
(F(1 + 2)), as observed with fondaparinux alone. Thrombin-
generation time and endogenous thrombin potential, which
were inhibited by fondaparinux, normalized up to 6 h after
rVIIa injection. In the second study 12 subjects received a
single s.c. dose of 7.5 mg idraparinux (which is 3 fold higher
than the currently recommended dose). The inhibition of
thrombin generation by idraparinux, as reflected by an
increased thrombin generation time (TGT) and decreased
level of prothrombin fragment 1 + 2 (F1+2), was partially
reversed by injection of rVIIa 3 h after idraparinux adminis-
tration. The administration of rVIIa 1 week after treatment
with idraparinux (when much lower, though still therapeutic,
doses of the pentasaccharide were present) resulted in an
nearly complete reversal of anticoagulation, reflected by nor-
malization of thrombin generation time and other markers of
thrombin generation. As mentioned, there are no controlled
trials in patients who present with pentasaccharide-induced
bleeding but there is some anecdotal experience suggesting
that rVIIa may indeed be able to stop bleeding in patients
anticoagulated with fondaparinux.

Vitamin K Antagonists
When interrupting the administration of VKA’s important
differences in the half-lives of the various agents (9 h for
acenocoumarol, 36–42 h for warfarin, and 90 h for phen-
procoumon, respectively) need to be taken into account [39].
The most straightforward intervention to counteract the
effect of VKA’s is the administration of vitamin K [40]. There
is quite some debate on the use of vitamin K in patients with
a too high INR but no signs of bleeding. However, a recent
randomized controlled trial did not find any difference in
bleeding or other complications in nonbleeding patients with
INR values of 4.5 to 10 that were treated with vitamin K or
placebo [41]. In patients with clinically significant bleeding
222 M. Levi

administration of vitamin K is crucial to reverse the antico-

agulant effect of VKA’s. Vitamin K can be given orally and
intravenously, whereas the parenteral route has the advan-
tage of a more rapid onset of the treatment [42]. After the
administration of i.v. vitamin K, within 2 h the INR will start
to drop and will be completely normalized within 12–16 h
[43], whereas after oral administration it will take up to 24 h
to normalize the INR [40]. Intramuscular injections of vita-
min K should be avoided in patients who are anticoagulated
and subcutaneous administration of vitamin K results in a
less predictable bioavailability [42]. A potential concern with
the use of parenteral vitamin K is the occurrence of anaphy-
lactic reactions, although the incidence of this complication is
very low, in particular with the more modern micelle prepara-
tions [44].
In case of very serious or even life-threatening bleeding,
immediate correction of the INR is mandatory and can be
achieved by the administration of vitamin K-dependent
coagulation factors. Theoretically, these factors are present in
fresh frozen plasma, however, the amount of plasma that is
required to correct the INR is very large, carries the risk of
fluid overload, and will probably take hours to administer
[45]. Therefore, prothrombin complex concentrates (PCC’s),
containing all vitamin K-dependent coagulation factors, are
more useful. Although PCC’s can indeed be given using fixed
dose schemes, it has been shown that individualized dosing
regimens based on INR at presentation and body weight are
more effective [46]. In a prospective study in patients using
VKA and presenting with bleeding also found that PCC’s
resulted in at least satisfactory and sustained hemostasis in
98 % [47]. In recent years the safety of PCC’s, in particular
regarding the transmission of blood-borne infectious dis-
eases, has markedly improved owing to several techniques,
such as pasteurization, nanofiltration, and addition of solvent
detergent. The risk of disseminated intravascular coagulation
(DIC) due to traces of activated coagulation factors in PCC’s
comes from older literature and modern PCC’s seem not to
be associated with eliciting DIC [48].
 Chapter 7. Management of Bleeding Complications 223

New Direct Factor Xa Inhibitors

In recent years a large number of new antithrombotic agents
has been developed and tested in clinical trials and many of
these new agents will become available for clinical practice in
the very near future [49]. The need for new anticoagulant
agents is quite obvious; Firstly, the current agents are insuffi-
ciently effective. For example 10–15 % of patients undergo-
ing major orthopedic surgery develop venous
thromboembolism, despite prophylaxis with low molecular
weight (LMW) heparin [50]. Furthermore, the available anti-
coagulants are relatively unsafe, mostly due to the occurrence
of bleeding as discussed hereabove. Lastly, current
anticoagulant agents are often cumbersome with regards to
their clinical use, requiring repeated laboratory control and
frequent dose adjustments. Increasing knowledge on the
function of the haemostatic system in vivo has resulted in a
new generation of anticoagulant agents.
Some of these new class of anticoagulants are directed at
factor Xa. Prototypes of these agents are rivaroxaban and
apixaban, which have shown promising results in clinical
studies [51, 52]. In trials in patients with acute venous throm-
boembolism rivaroxaban and apixaban were as effective as
LMW heparin but rivaroxaban was associated with a lower
incidence of bleeding complications (2.2 % versus 8.8 %) [53,
54]. Rivaroxaban was also studied in patients with acute coro-
nary syndromes and showed a dose-dependent efficacy but
also increased rates of major bleeding at higher doses [55].
Similarly, apixaban showed a similar pattern and exhibited
2.5 fold increased bleeding rates, in particular in patients
using simultaneous anti-platelet agents [56]. Taken together,
compared to LMW heparin direct factor Xa inhibitors result
at doses achieving equivalent efficacy a lower bleeding risk
and at doses achieving higher efficacy a similar bleeding risk.
This means that for some clinical situations these drugs may
represent an important improvement, however, the risk of
(major) bleeding is still present. Recently it was shown that
the administration of prothrombin complex concentrate
224 M. Levi

Thrombin generation
ETP
200

PCC
150
%

100

50

placebo
0
in
e

1h

2h

4h

8h
in

h
in

24
T=

m
el

15

30
s
Ba

Time

Rivaroxaban 20mg PCC or

placebo
BID 2,5 days

Figure 7.1 Restoration of rivaroxaban-induced impaired thrombin

generation, measured by endogenous thrombin potential (ETP), by
administration of prothrombin complex concentrates (squares) as
compared to placebo (circles) in healthy volunteers. Mean ± SD are
reported, the difference between the two groups is statistically
significant (p < 0.001 Repeated Measures ANOVA)

(PCC) resulted in a correction of the prolonged prothrombin

time and restored depressed thrombin generation after riva-
roxaban treatment in a controlled trial in healthy human
subjects (Fig. 7.1) [57]. The effect of PCC’s on reversal of the
anticoagulant effect of oral factor Xa inhibitors was con-
firmed in a series of experiments in animals and human sub-
jects [58–60]. The clinical efficacy in bleeding patients,
however, needs to be established.

Direct Thrombin Inhibitors

Another important group of new anticoagulants is the class
of direct thrombin inhibitors. Thrombin is the central enzyme
in the coagulation process, not only mediating the conversion
 Chapter 7. Management of Bleeding Complications 225

of fibrinogen to fibrin, but also being the most important

physiological activator of platelets and various other coagula-
tion factors. Inhibition of thrombin can be achieved by
administration of heparin, but in view of the limited capabil-
ity of the heparin-antithrombin complex to inhibit surface-
bound thrombin, new antithrombin-independent
anticoagulants have been developed [61]. Prototype of these
thrombin inhibitors is hirudin, originally derived from the
saliva from leeches (hirudo medicinalis) and nowadays pro-
duced by recombinant technology. Melagatran is a synthetic
thrombin inhibitor, which has predictable pharmacokinetic
properties and can thus be used in a fixed dose [62].
Moreover, the pro-drug ximelagatran is relatively quickly
absorbed after oral ingestion and results in a sufficient sys-
temic availability, rendering this agent suitable for long-term
use as oral anticoagulant. Despite clinical trials on prevention
and treatment of venous thromboembolism and in patients
with atrial fibrillation showing a promising efficacy of ximela-
gatran, the compound has been withdrawn by the manufac-
turer, due to the occurrence of enhanced liver enzymes in
6–7 % of patients. Recently, dabigatran, also a direct throm-
bin inhibitor with good and relatively stable bioavailability
after oral ingestion, has been introduced and licensed for
prevention of venous thromboembolism after orthopedic
surgery. Indeed, clinical trials evaluating dabigatran against
LMW heparin in patients undergoing major othropedic sur-
gery show similar or slightly better efficacy of the direct
thrombin inhibtor and similar bleeding rates [63, 64]. The
largest group of patients using long-term anticoagulants,
however, are those with atrial fibrillation. In these patients
dabigatran (150 mg twice daily) showed a significantly lower
rate of thromboembolic complications compared to warfarin
(relative risk 0.66; 95 % confidence interval 0.53–0.82) but
also a slightly lower risk of major hemorrhage (3.11 %/year
in the dabigatran group versus 3.36 %/year in the warfarin
group) [65]. Based on these findings and if confirmed by
other ongoing major trials, it may be quite likely that in the
future oral anticoagulant treatment with vitamin K antagonists
226 M. Levi

is going to be replaced by treatment with directly acting anti-

coagulants, such as direct thrombin inhibitors. However, the
risk of major bleeding is still relatively large and requires
adequate management strategies.
For each of the direct thrombin inhibitors no established
antidote is available in case of serious bleeding complicating
the anticoagulant treatment. Again, the half-life of most of
the agents is relatively short, hence in case of less serious
bleeding interruption of treatment will be sufficient to
reverse the anticoagulant effect. However, if immediate
reversal is required, it is not clear which would be the best
strategy. In a controlled clinical study in healthy subjects the
melagatran-induced effects on aPTT, thrombin generation
and platelet activation were not affected by the administra-
tion of rVIIa [66]. Also, in human subjects challenged with
dabigatran there was no reversal of the anticoagulation by
administration of prothrombin complex concentrates [57].
An experimental study of intracerebral hematoma in
dabigatran-treated rats, however, demonstrated that rela-
tively high doses of prothrombin complex concentrates were
able to reduce hematoma volume [67].

Aspirin
Aspirin is effective in the secondary prevention of athero-
thrombotic disease, in particular coronary artery disease,
cerebrovascular thromboembolism and peripheral arterial
disease [68]. As a consequence, aspirin is one of the most
widely used agents in the Western world. Aspirin increases
the risk of bleeding, in particular gastro-intestinal bleeding,
and has been associated with a small but consistent increase
in intracerebral hemorrhage. In addition, it has been shown
that the use of aspirin is associated with increased periopera-
tive blood loss in major procedures, although this does not
necessarily translates into clinically relevant endpoints, such
as the requirement for transfusion or re-operation [69]. Over
 Chapter 7. Management of Bleeding Complications 227

the last years the approach to the patient who uses aspirin
and who presents with bleeding or needs to undergo an inva-
sive procedure has changed considerably. In fact, in current
clinical practice bleeding can almost always be managed with
local hemostatic procedures or conservative strategies with-
out interrupting aspirin and also most invasive procedures do
not require the cessation of aspirin when adequate attention
is given to local hemostasis. In contrast, interruption of aspi-
rin has been associated with an increased risk of thromboem-
bolic complications, potentially due to a rebound
hypercoagulability. Obviously, in special clinical circumstances,
such as intracranial bleeding or the need to undergo a neuro-
surgical or ophthalmic procedure, the anti-hemostatic effect
of aspirin needs to be reversed immediately. The most rigor-
ous measure to achieve that is the administration of platelet
concentrate after cessation of aspirin. Another approach is
the administration of de-amino d-arginin vasopressin
(DDAVP, desmopressin). DDAVP is a vasopressin analogue
that despite minor molecular differences has retained its
antidiuretic properties but has much less vaso-active effects
[70]. DDAVP induces release of the contents of the endothe-
lial cell associated Weibel Palade bodies, including von
Willebrand factor. Hence, the administration of DDAVP
results in a marked increase in the plasma concentration of
von Willebrand factor (and associated coagulation factor
VIII) and (also by yet unexplained additional mechanisms) a
remarkable augmentation of primary hemostasis as a conse-
quence. DDAVP is effective in patients with mild hemophilia
A or von Willebrand’s disease and in patients with qualitative
platelet defects, such as in uremia or liver cirrhosis. DDAVP
seems also capable of correcting the aspirin-induced platelet
dysfunction, although large clinical studies employing rele-
vant outcome parameters are missing [71]. The combined
effect of platelet concentrate and subsequent administration
of DDAVP has also been advocated to correct the aspirin
effect on platelets. The standard dose of DDAVP is 0.3–0.4 μg/
kg in 100 ml saline over 30 min and its effect is immediate.
228 M. Levi

Thienopyridine Derivatives
Clopidogrel, prasugrel and ticagrelor belong to the class of
thienopyridine derivatives, which act by blocking the adenos-
ine diphosphate (ADP) receptor on the platelet. Clinical
studies have shown that clopidogrel is as good as aspirin in
the secondary prevention of atherothrombotic events [72].
Importantly, the combination of aspirin and clopidogrel is
vastly superior over aspirin alone in patients who have
received intracoronary stents or in other patients with high
risk coronary artery disease. There is ample evidence that
dual platelet inhibition of aspirin plus clopidogrel has a sig-
nificantly higher efficacy than aspirin alone in patients with
acute coronary syndromes who have undergone coronary
interventions for at least a year (and possibly longer) after
the event. However, the increased efficacy of the combined
use of aspirin and clopidogrel is also associated with a signifi-
cantly higher bleeding risk [73]. Prasugrel is another thieno-
pyridine derivative that after rapid and almost complete
absorption after oral ingestion irreversibly binds to the ADP
receptor. Prasugrel has a stronger anti-platelet effect than
clopidogrel because of more effective metabolism and less
dependence of cytochrome P450 enzymes that may be sub-
ject to genetic polymorphisms [74]. Prasugrel was shown to
be more effective than clopidogrel in preventing ischemic
events in patients with ST elevation myocardial infarction
undergoing primary percutaneous coronary interventions
(with or without stent) [75]. Rates of major bleeding were
similar between clopidogrel and prasugrel, however, the rate
of serious bleeding in patients requiring emergency coronary
artery bypass grafting (CABG) was higher in the prasugrel
group. In patients with acute coronary syndromes prasugrel
was also more effective than clopidogrel in preventing car-
diovascular death, myocardial infarction and stroke, however,
major bleeding rates were higher in the prasugrel group
(2.4 % versus 1.8 %) [76]. Of note, this disadvantage of pra-
sugrel did not outweigh the efficacy benefit, and the net clini-
cal benefit (defined as the efficacy gain minus the increased
 Chapter 7. Management of Bleeding Complications 229

risk of major bleeding) was preserved in favour of prasugrel.

Ticagrelor is a cyclopentyltriazolopyrimidine that differs
from thienopyridines (ticlopidin, clopidogrel, prasugrel), as
ticagrelor is not a prodrug requiring active biotransformation
by cytochromes in the liver and thus is characterized by a
more rapid, more effective and more consistent platelet inhi-
bition than ticlopidin or clopidogrel [77]. The Platelet
Inhibition and Patient Outcomes (PLATO) trial determined
whether ticagrelor was superior to clopidogrel for the
prevention of vascular events and death in a broad popula-
tion of patients presenting with an acute coronary syndrome
[78]. treatment with ticagrelor as compared with clopidogrel
significantly reduced the rate of death from vascular causes,
myocardial infarction, or stroke. The ticagrelor and clopido-
grel groups did not differ significantly with regard to the rates
of major bleeding as defined in the trial or according to the
Thrombolysis in Myocardial Infarction (TIMI) criteria. The
two treatment groups did not differ significantly in the rates
of CABG-related major bleeding or bleeding requiring trans-
fusion of red cells. However, in the ticagrelor group, there was
a higher rate of non–CABG-related major bleeding accord-
ing to the study criteria and the TIMI criteria. With ticagrelor
as compared with clopidogrel, there were more episodes of
intracranial bleeding, including fatal intracranial bleeding.
However, there were fewer episodes of other types of fatal
bleeding in the ticagrelor group. Recently, a fourth thieno-
pyridine derivative has been introduced: cangrelor. The
advantage of this compound over the other members of this
group is the faster onset of action, which may be critical in
acute coronary syndromes. However, two major clinical trials
comparing cangrelor with clopidogrel in patients undergoing
percutaneous coronary interventions did not show a higher
efficacy of cangrelor but did demonstrate a significantly
higher risk of bleeding [79, 80]. Taken together, dual platelet
inhibition, in particular with clopidogrel or even more out-
spoken with prasugrel, is highly effective in high risk patients
with coronary artery disease but the bleeding risk with dual
platelet inhibition is something to take into account and
230 M. Levi

strategies to reverse the antiplatelet effect may be warranted

in case of serious bleeding.
The decision whether or not the interrupt or even reverse
antithrombotic treatment with dual platelet inhibition in case
of serious bleeding or the need to perform an invasive proce-
dure will depend on the specific clinical situation but also on
the indication for the antithrombotic treatment (see above).
Especially in patients with recent implantation of an intracoro-
nary stent (in the last 6–12 weeks), cardiologists will often not
or only reluctantly agree with cessation of treatment [81]. In
this period re-endothelization of the stent has not yet occurred
and the patient is very vulnerable to acute thrombotic occlu-
sion of the stent. In patients with drug-eluting stents this period
may be even longer. If, however, the decision is made to stop
and even reverse the treatment with aspirin and clopidogrel,
administration of platelet concentrate is probably the best way
to correct the hemostatic defect [82]. In addition, DDAVP was
shown to correct the defect in platelet aggregation caused by
clopidogrel, so this may be another option [83].

Conclusion
Conventional anticoagulant treatment can be reversed by spe-
cific interventions when the clinical situation requires immedi-
ate correction of hemostasis. For the new generation of
anticoagulants, no specific antidotes are available, although
some interventions are promising but need further evaluation.
Antiplatelet therapy with aspirin, alone or in combination with
thienopyridine derivatives, such as clopidogrel and prasugrel,
can be reversed but this is often not required and sometimes
not desirable in view of the indication for this treatment.

References
1. Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ.
Antithrombotic and thrombolytic therapy: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines
(8th Edition). Chest. 2008;133(6 Suppl):110S–2.